The innate immune response is the first line of defense against viral pathogens. In the absence of an antiviral innate response, viral replication is uncontrolled and lethal disseminated infection can occur. Pattern recognition receptors (PRRs) are critically involved in the development of innate anti-viral immunity. Innate immune activation by viruses may occur via cell surface, intracellular and/or cytosolic pattern recognition receptors. These receptors may sense different viral components and may activate unique downstream pathways to generate anti-viral immunity. We hypothesize that PRR interaction with herpes viruses activates IRF1-dependent downstream pathways in innate immune cells that are critically involved in the control of the inflammatory response to HSV infection. In this proposal we will; 1. Define the role of TLRs in HSV innate immune responses 2. Define the mechanism of IRF1 regulation of innate immunity and protection from lethal HSV encephalitis 3. Define the role of HSV in TLR signaling and IRF1 activation of pro- and anti-inflammatory anti-viral pathways We will define the PRRs, particularly TLRs, that sense HSV infection and trigger innate immune responses. We will define the mechanism of IRF1 regulated HSV responses by defining the receptors and mediators upstream of IRF1 activation as well as the target genes and factors downstream of IRF1 in HSV infection. These studies are complemented by studies of Dr. Fitzgerald (Project 2) examining a unique intracellular virus sensing pathway that is also dependent on IRF1. We will utilize pathway specific reagents generated by Dr. Fitzgerald as well as viruses and viral mutants generated by Dr. Knipe (Project 3) to define the mechanisms of PRR-virus interactions leading to IRF1 activation. The role of PRR pathways in HSV immunity will be extended to human patients by studies conducted by Dr. Finberg (Project 4). These studies will further the overall goals of the Program Project by defining the cells, receptors and viral components that are critically involved in the initiation of viral immunity and protection of the host from lethal encephalitis. RELEVANCE (See Instructions): The failure to mount anti-viral responses can have devastating consequences. Nevertheless, innate immunity is a double-edged sword as excess inflammatory activation may itself harm the patient. A deeper understanding of receptor-virus interactions and the molecular events that are triggered when virus recognition occurs is critical for the development and testing of therapeutic interventions that will both protect from excess inflammation and promote anti-viral immunity.